Scientists have found for the first time a way to rev
up a potent "anti-aging" enzyme inliving cells, an advance they said could speed the development
of drugs to extendhuman life span and prevent a wide range of geriatric
diseases.

The novel approach has significantly increased the life
spans of yeast and human cells in laboratory dishes and extended the lives
of flies and worms --organisms that, on the level of molecular biology,
age much as humans do. Indeed, the researchers said, the compounds
seem to have the same anti-aging effect as a drastic reduction in calories,
the only strategy ever proven to extend life in mammals but one that most
people find difficult to stick to.

It is too soon to say whether the latest findings will
ever make the leap from the labbench to the geriatrics clinic -- though some may choose
not to wait: Of all thecompounds the researchers tested, the one that boosted
the anti-aging enzyme themost was resveratrol, an ingredient in red wine that
has been credited with thatbeverage's ability to lower the risk of heart disease.

But the findings strengthen an increasingly popular notion
among many scientists thatthe cellular enzymes at the core of the experiments --
called sirtuins -- are universalregulators of aging in virtually all living organisms
and represent a prime target for newanti-aging drugs.

"It's looking like these sirtuins serve as guardians of
the cell," said Harvard MedicalSchool researcher David Sinclair, who led the new work
published in yesterday'sonline edition of the journal Nature. "These enzymes
allow cells to survive damageand delay cell death."

Now the race is on, Sinclair said, to find the most potent
sirtuin stimulators -- orcreate synthetic ones -- and test their ability to extend
the lives not only of cells, fliesand worms but also of mice, monkeys and humans.

Other researchers were more cautious, warning that aging
is a complex and poorlyunderstood process that is unlikely to be slowed by any
single drug. As promising asthe research may appear today, they said, sirtuin would
not be the first fountain ofyouth to prove a mirage.

"Let's face it, aging isn't the same in humans and yeast,"
said Jef Boeke, a yeastgeneticist at the Johns Hopkins University School of
Medicine. Besides, he said,sirtuins are potent molecules, and in cranking them up,
"one would have to be verycareful about potential side effects." The new study
caps a three-year string ofdiscoveries involving sirtuins (pronounced sir-TOO-ins),
a class of enzymes that arefound in virtually every organism, including bacteria,
plants and people. As with allenzymes, their job is to promote essential biochemical
reactions inside cells.

At first scientists thought sirtuins spent most of their
time pulling key molecules off theproteins that surround DNA -- part of the process by
which cells turn their genes onand off.

But recently researchers learned that sirtuins are also
involved in processes with muchmore medical -- and commercial -- potential: They are
part of a feedback system thatenhances cell survival during times of stress, especially
if that stress is a lack of food.

For years researchers have known that life span can be
extended by 50 percent ormore in many kinds of creatures, including flies, worms
and mice, if the animal is fed adiet that is nutritious but contains about 30 percent
fewer calories than usual. Recentlyscientists found that the life-extending benefits of
calorie restriction do not occur if theanimal has been genetically altered to lack sirtuins,
indicating these enzymes arecrucial to this process.

Now scientists are coming to understand sirtuins' role
in that life-extending response.In people, they seem to halt the normal cellular cycle
that ends with old cellscommitting suicide and instead help rejuvenate them by
beefing up their DNA repairprocesses and stimulating production of protective antioxidants.

"What we think is that if a cell is at a point of deciding
whether to live or die, thesesirtuins push toward the survival mode and let the cell
try a little harder and longer tofix itself," said Sinclair, who has a financial stake
in a new effort to developsirtuin-related products with BIOMOL Research Laboratories
of Plymouth Meeting,Pa.

Leonard Guarente, a researcher at the Massachusetts Institute
of Technology inCambridge, is also enthusiastic about the compounds'
potential as anti-aging aids.

"We're very keen on the idea that this is it" -- that
sirtuins are the central regulator ofthe aging process -- Guarente said. He is a founder of
Elixir Pharmaceuticals ofCambridge, Mass., which, like Sinclair and BIOMOL, hopes
to capitalize onchemicals that can boost sirtuin activity.

The goal is to make drugs or nutritional supplements that
can fool the body intothinking it's living on a radically calorie-reduced diet,
in effect allowing people to eattheir cake and live longer, too.

The new report from Sinclair's team is the first to show
that it is indeed possible totweak the sirtuin pathway. The group screened a large
number of biologically activechemicals -- simple compounds that can be made into drugs
with relative ease. Theyfound several that increase sirtuin activity at least
two-fold, including resveratrol.

When they added some of these compounds to yeast cells
growing in culture dishes,the cells produced 70 percent more daughter cells than
normal -- a common measureof yeast youthfulness.

Human cells seemed to benefit, too. Those treated with
sirtuin boosters enjoyed longlives in laboratory dishes even after being exposed to
ionizing radiation, whichdamages DNA and usually shortens a cell's lifespan.

And in experiments not yet completed, Sinclair said, the
compounds have shownevidence of being able to extend the life spans of two
full-blown organisms: thesoil-dwelling nematode worm known as C. elegans and the
common fruit fly. Bothare popular stand-ins with scientists trying to understand
human biological processes.

Sinclair said his group plans to start feeding sirtuin
boosters to mice in the next fewmonths and then move up to testing in monkeys. The immediate
goal in people wouldbe to slow the progression of diseases of aging such
as Alzheimer's, because a moregeneric slowing of the aging process could take decades
to prove.

But others warned against exaggerated expectations. Richard
Weindruch, agerontologist and expert in calorie restriction at the
University of Wisconsin inMadison, said the work was "very interesting and deserves
to be carefully explored inmammals." But he questioned the relevance of the yeast
experiments -- which, strictlyspeaking, measured not life span but the number of times
a yeast cell could divide andproduce daughter cells.

"Clearly, numbers of generations are related to time,
but it's not the same in my mindas following a single animal over its lifetime," Weindruch
said. Indeed, he noted,"What they are really looking at here is increased proliferative
capacity," which he andothers noted is akin to cancer.

David Finkelstein, an expert in metabolic regulation at
the National Institute on Aging,which funded some of Sinclair's work, said the work was
"very nice science" but alsowarned against leaping to conclusions. "We have results
in a lower organism," he said,"and at this point, there's a lot of hand waving because
of how little we know."

Finkelstein also advised against taking the resveratrol
results too literally.

"Would the National Institute on Aging recommend you drink
red wine every day?The answer is 'no,' " he said. "If you were to add a
glass of red wine every daywithout changing your caloric intake, you're going to
gain weight. And we know -- weknow -- that if you gain weight, that's going to be harmful
while this 'benefit' is abenefit that may or may not occur."

"People are always looking for a quick fix," Finkelstein
said. "Tell people to eat ahealthy diet."

Biologists have found a class of chemicals thatthey hope will make people live longer by activatingan ancient survival reflex.

One chemical, a natural substance known asresveratrol, is found in red wines, particularly those
made in cooler climates like thatof New York.

The finding could help explain the so-called French paradox
-- the fact that theFrench consume fatty foods considered threatening to
the heart but live as long asanyone else.

Besides the wine connection, the finding has the attraction
of stemming fromfundamental research in the biology of aging. However,
the new chemicals have notyet been tested even in mice, let alone people, and even
if they work in humans itwill be many years before any drug based on the new findings
becomes available.

The possible benefits could be significant. The chemicals
are designed to mimic theeffect of a low-calorie diet, which is known to lengthen
the life span of rodents.Scientists involved in the research say human life span
could be extended by 30percent if people respond to the chemicals the way rats
and mice do to low calories.Even someone who started at age 50 to take one of the
new chemicals couldexpect to gain an extra 10 years of life, said Dr. Leonard
Guarente of theMassachusetts Institute of Technology, one of the pioneers
of the new research.

The result was announced last week at a scientific conference
in Arolla, a smallvillage in the Swiss Alps, by Dr. David A. Sinclair of
Harvard Medical School. It waspublished electronically Sunday in the journal Nature.

The new development has roused the enthusiasm of many
biologists who studyaging because caloric restriction, the process supposedly
mimicked by thechemicals, is the one intervention known to increase
longevity in laboratory animals.A calorically restricted diet -- including all necessary
nutrients but 30 percent fewercalories than usual -- has been found to extend the life
span of rodents by 30percent to 50 percent. Scientists hope, but do not yet
know, that the same will betrue in people.

A similar mechanism exists in simpler forms of life, which
has led biologists tobelieve that they are looking at an ancient strategy,
formed early in evolution andbuilt into all animals. The strategy allows an organism
to live longer and postponereproduction when food is scarce, and to start breeding
when conditions improve.

Two experiments to see if caloric restriction extends
life span in monkeys are atabout their halfway point -- rhesus monkeys live about
25 years in captivity -- andthe signs so far are promising, though not yet statistically
significant. But even ifcaloric restriction should extend people's life span,
the current epidemic of obesitysuggests how hard it would be for most people to stick
with a diet containing 30percent fewer calories than generally recommended.

Biologists have therefore been hoping to find some chemical
or drug that wouldmimic caloric restriction in people by tripping the same
genetic circuitry that areduced-calorie diet does and provide the gain without
the pain. Sinclair and hischief co-author, Dr. Konrad T. Howitz of Biomol Research
Laboratories in PlymouthMeeting, Pa., say they have succeeded in finding a class
of drugs that mimiccaloric restriction in two standard laboratory organisms,
yeast and fruit flies. Bothmice and humans have counterpart genes that are assumed
to work in a similarway, though this remains to be proved.

Independently, Elixir Pharmaceuticals of Cambridge, Mass.,
had found a differentset of chemicals that mimic caloric restriction, said
Ed Cannon, Elixir's chiefexecutive. Because of testing and regulatory requirements,
he said, his company is"eight to 10 years away from having an approved drug."

After presenting his results for the first time, Sinclair
said in an interview from Arolla,"I've been waiting for this all my life."

"I like to be cautious," he said, "but even as a scientist
it is looking extremelypromising."

So far Sinclair and his colleagues have shown only that
resveratrol, the chemicalfound in red wine, prolongs life span in yeast, a fungus,
by 70 percent. But acolleague, Dr. Mark Tatar of Brown University, has shown,
in a report yet to bepublished, that the compound has similar effects in fruit
flies. The National Instituteof Aging, which sponsored Sinclair's research, plans
to start a mouse study later inthe year.

Despite the years of testing that will be needed to prove
that resveratrol has anyeffect in people, many of the scientists involved in
the research have already starteddrinking red wine. "One glass of red wine a day is a
good recommendation. That'swhat I do now," Sinclair said. Resveratrol, he said,
is unstable on exposure to the airand "goes off within a day of popping the cork."

Tatar, asked if he had changed his drinking habits, said,
"No, I have alwayspreferred red wine to white."

Health authorities have not yet had time to make a detailed
evaluation of theresearch. Dr. David Finkelstein, the project officer
at the National Institute of Aging,said he would not advise anyone to start drinking red
wine.

"At this point we have no indication that there will be
a benefit in people," Finkelsteinsaid, adding that the calories in a glass of wine could
lead to weight gain.

Dr. Toren Finkel, who is in charge of cardiovascular research
at the National Heart,Lung and Blood Institute, said: "I would be cautious
in sending out the message thatone glass of wine a day will make you live 10 years longer.
The concentration ofresveratrol in different wine differs. As a drug, it
is not ready for prime time." But theconcept of a drug that mimics caloric restriction "is
a great idea," he said.

Sinclair said that he and Howitz were working on chemical
modifications ofresveratrol that would be more stable. Ownership of the
patent will be split evenlybetween their parent institutions, Harvard Medical School
and Biomol.

Resveratrol is synthesized by plants in response to stress
like lack of nutrients andfungal infection. It exists in the skin of both red and
white grapes but is found inamounts 10 times as high in red wine as in white because
of the differentmanufacturing process.

According to "The Oxford Companion to Wine" pinot noir
tends to have high levels ofthe chemical, cabernet sauvignon lower levels. "Wines
produced in cooler regions orareas with greater disease pressure such as Burgundy
and New York often havemore resveratrol," the book says, whereas wines from
drier climates like Californiaor Australia have less.